Heymann nephritis is a well-known inducible rat model for human membranous glomerulonephritis (Heymann, W. et al., Proc. Soc. Exp. Biol. Med. 100:660 (1959); Heymann, W. et al., Ann. N.Y. Acad. Sci. 124:310 (1965)). Heymann nephritis is induced in the rat by immunizing with whole kidney homogenates incorporated in complete Freund's adjuvant. The antigen responsible for the disease (termed a "nephritogen") was found to be contained in a membrane preparation derived from tubular brush border regions of proximal convoluted tubules (known as Fx1A), and a more purified fraction (known as RTE.alpha.5) was also reported to be nephritogenic (Edgington, T. S. et al., J. Exp. Med. 127:555 (1968)).
Other workers have identified nephritogenic glycoproteins in such kidney tubule preparations. For example, Naruse, T., et al., Lab. Invest. 33:141 (1975), described the isolation and purification of a 8.4S tubular glycoprotein which was nephritogenic. Kerjaschki and Farquhar isolated a glycoprotein having an estimated molecular weight of 330,000 daltons (gp330) which was a pathogenic antigen of Heymann nephritis. This brush border membrane glycoprotein was purified and characterized (Kerjaschki and Farquhar, Kidney International 30:229 (1986)). Other workers have reported that a 600,000 dalton glycoprotein (gp600), also a component of Fx1A, can induce this disease (Makker, S. P. and Singh, A. K., Lab. Invest. 50:287 (1984)). In total, four subunits of gp600 (gp330, gp140, gp110 and gp70) have been isolated and shown to be nephritogenic (Singh, A. K. and Schwartz, N. M., Clin. Immunol. Immunopathol. 48:61-77 (1988); Makker, S. P. and Singh, A. K., Lab. Invest. 50:287 (1984)). A 400 kD protein in the brush borders of human kidney tubules, which is similar to gp330, has also be identified (Kerjaschki, D. et al., Am. J. Pathol. 129: 183 (1987 )).
The pathophysiological role of gp330 in "in situ" immune complex formatin, which results in glomerulonephritis, is not defined. However, it is believed that the deposit formation is initiated by the reaction of autoantibodies with gp330 on the surface of podocytes with the subsequent shedding of complexes into the basement membrane (Andres, G. et al., Lab. Invest. 55:520 (1986); Von Damme, B. J. C. et al., Lab. Invest. 38:502 (1978); Couser, W. G. et al., J. Clin. Invest. 62:1275 (1987)).
Gp330 is found on the apical plasmalemmal domain of said epithelial cells, in particular proximal renal tubules, glomerular podocytes, intestine, lung (type II pneumocytes), epidermis, and yolk sac (Doxsey, S. et al., J Cell Biol. 97:178a (1983); Chatelet, F. et al., Am. J. Pathol. 122:512 (1986)). Immuno-electron microscopic studies have shown that gp330 is concentrated in clathrin-coated pits (Bhan, A. K. et al., Lab. Invest. 53:421 (1986)). The coated pit appears to act as a molecular filter and mediates endocytic uptake of specific receptor proteins and their associated ligands. It is assumed that gp330, like a number of membrane receptors, is concentrated in coated pits and brings its ligand into the cell by a mechanisms known as "receptor-mediated endocytosis" (Brown, M. S. and Goldstein, J. L., Science 53:421 (1986); Goldstein, J. L. et al., Nature 270:679 (1979)).
Despite the advances provided by the study of Heymann nephritis, a need continues to exist for plentiful sources of polypeptides and glycoproteins implicated in autoimmune kidney disease to allow the development of diagnostic tools and novel forms of therapy for human membranous glomerulonephritis and other conditions.